Heterocyclic compounds

ABSTRACT

Compounds of the formula I, ##STR1## are NMDA antagonists and useful in the treatment and prevention of nervous system related pathological conditions resulting from overstimulation by excitatory amino acids. Methods for their preparation and pharmaceutical compositions containing them are also comprised according to the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a 371 of international application PCT/SE94/01211 with aninternational filing date of Dec. 16, 1994, claiming priority to Swedishapplications 93 04 269-5 (filed Dec. 22, 1993); 94 00 968-5 (filed Mar.23, 1994) and 94 02 122-7 (filed Jun. 16, 1994).

FIELD OF THE INVENTION

The present invention relates to new quinoline compounds, to methods fortheir preparation, their use, and pharmaceutical compositions thereof.The compounds are antagonists of N-methyl-D-aspartate (NMDA) receptorsand are useful in the treatment of disorders known to be responsive toblockade of the NMDA excitatory amino acid receptor. Accordingly theyare especially useful in the treatment of disorders such as pain,anxiety, and cerebral ischemia and as an anaesthetic.

BACKGROUND OF THE INVENTION

The endogenous acidic amino acids, L-glutamate and L-aspartate, havebeen established as major excitatory neurotransmitters. The action ofthese excitatory amino acids is mediated by several distinct receptorsubtypes of which one is the N-methyl-D-aspartate (NMDA) receptor.Excessive activation of the NMDA receptor complex is implicated in anumber of neuropathological conditions and hence antagonists of thisreceptor complex have a potential for providing new therapeutic agents.In animal models of human disorders it has been shown that certain knownNMDA antagonists have anticonvulsant activity cf. e.g. Lehmann et al. J.Pharmacol. Exp. Therap., 246, 65 (1988). This implicates the usefulnessof NMDA antagonists as antiepileptic agents. Known NMDA antagonists alsogive protection against neuronal cell death caused by excessivestimulation cf. Boast et al. Brain Res., 442, 345 (1982). Hence, theseagents may be used in the treatment of ischemic and hypoxic conditionsand also of neurodegenerative disorders e.g. Alzheimer's disease. Byintrathecal injection known NMDA antagonists have exhibited analgeticactivity cf. Cahusac et al. Neuropharmacology, 23, 719 (1984). Theantagonists may also be beneficial in the treatment of migraine,anxiety, hearing loss, motor neuron diseases, trauma from infections andillness linked to lutenizing hormone secretion. NMDA antagonists with anaryl-spaced phosphono α-amino acid structure have been described in e.g.J. Med. Chem., 32, 1580 (1989) and in J. Med. Chem., 36, 331 (1993).

OUTLINE OF THE INVENTION

The present invention is concerned with a group of novel NMDAantagonists, methods to prepare them, pharmaceutical compositionscontaining them and therapeutic use of the antagonists to prevent and/orrelieve the physiological effects induced by overstimulation ofexcitatory amino acid receptors of the nervous system.

The novel compounds of the invention exhibit the following structuralformula I ##STR2## in which m is 0,1 or 2; n is 1,2 or 3; and R¹ and R²are, independently and being the same or different, hydrogen, C₁ -C₇alkyl, C₂ -C₇ alkenyl, C₄ -C₇ alkadienyl, C₆ aryl, C₆ aryl-C₁ -C₇ alkyl,C₁ -C₇ alkoxy, C₁ -C₇ alkanoyl, C₁ -C₇ alkanoyloxy, C₆ aroyl, C₆aroyloxy, C₆ aryl-C₁ -C₇ alkanoyl, C₁ -C₇ alkoxycarbonyl, C₆ aryl-C₁ -C₇alkoxycarbonyl, C₁ -C₇ alkylthio, trifluoromethyl, trifluoromethoxy, C₁-C₇ alkylsulfonyl-amino, C₁ -C₇ alkylamino, C₁ -C₇ alkanoylamino, nitro,halogen, or R₁ and R₂ are taken together, C₁ -C₇ alkylene, C₂ -C₇alkenylene or C₄ -C₇ alkadienylene; and the pharmaceutically acceptableesters and salts, including hydrates, of compounds according to theformula (I).

Preferred compounds of the present invention are compounds according tothe formula (II) ##STR3## wherein R¹ and R² are as defined above.

The compounds of the invention are α-amino acid derivatives and thus thecompounds of the invention include not only the individual enantiomers,but mixtures of enantiomers, including racemic mixtures. The R-isomer isthe preferred isomeric form.

The general definitions used herein have the following meaning in thecontext of the invention.

When referring to a hydrocarbon moiety and hereinafter in connectionwith organic groups, we define such with up to and including 7 carbonatoms, more preferably up to and including 4 carbon atoms.

Preferred alkyl groups according to the invention are C₁ -C₄ alkyl,represented by for example methyl, ethyl, propyl or butyl. Also withinthe scope are branched alkyl groups, represented by for exampleisopropyl. Unless otherwise indicated, cycloalkyl groups may be used inplace of alkyl groups wherever mentioned herein.

When R¹ and R² are taken together, preferred alkylene groups accordingto the invention are C₂ -C₆ alkylene represented by for exampleethylene, propylene or butylene.

Preferred alkenyl groups are C₂ -C₄ alkenyl.

Preferred alkadienyl groups are C₄ -C₆ alkadienyl.

When R¹ and R² are taken together, preferred alkenylene groups accordingto the invention are C₂ -C₆ alkenylene, represented by for examplebutenylene.

When R¹ and R² are taken together, preferred alkadienylene groupsaccording to the invention are C₄ -C₆ alkadienylene, represented by forexample butadienylene.

Preferred C₆ aryl groups according to the invention are phenyl orsubstituted phenyl. The term "substituted phenyl" refers to phenylshaving one to three substituents selected from C₁ -C₇ alkyl, C₁ -C₇alkoxy, trifluoromethyl and halogen. A pyridyl, particularly 3-pyridyl,may be used in place of a C₆ aryl group.

Preferred C₆ aryl-lower alkyl groups according to the invention are C₆aryl-C₁ -C₄ -alkyl, C₆ aryl having the meaning as defined above,advantageously benzyl or 2-phenylethyl.

Preferred alkoxy groups according to the invention are C₁ -C₄ alkoxy,represented by for example, ethoxy, propoxy or methoxy.

Preferred alkanoyl groups according to the invention are C₂ -C₇alkanoyl, advantageously acetyl, propionyl, n-butyryl, isobutyryl orpivaloyl.

Preferrred alkanoyloxy groups according to the invention are C₂ -C₅alkanoyloxy advantageously acetoxy, propionyloxy, n- or i-butyryloxy orpivaloyloxy.

C₆ aroyl represents C₆ -arylcarbonyl. Preferred aroyl groups accordingto the invention are benzoyl or benzoyl substituted by one to threesubstituents selected from C₁ -C₇ alkyl, C₁ -C₇ alkoxy, trifluoromethyland halogen; or pyridylcarbonyl, particularly nicotinyl.

Preferred C₆ aroyloxy groups according to the invention are benzoyloxy,benzoyloxy substituted on the phenyl ring by C₁ -C₇ alkyl, halogen or C₁-C₇ alkoxy; or nicotinoyloxy.

Halogen is preferably fluorine and chlorine, but may also representbromine or iodine.

Preferred C₆ aryl-alkanoyl groups according to the invention are C₆aryl-C₁ -C₄ -alkanoyl, advantageously phenylacetyl or 3-phenylpropionyl.

Preferred alkoxycarbonyl groups according to the invention are C₁ -C₄alkoxycarbonyl, i.e. containing 1-4 carbon atoms in the alkoxy portion,represented by for example: methoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl or ethoxycarbonyl.

C₆ aryl-C₁ -C₇ -alkoxycarbonyl represents preferably benzyloxycarbonyl.

A pharmaceutical acceptable ester within the context of the presentinvention represent an ester of a compound of the invention having acarboxy group, preferably a carboxylic acid prodrug ester that may beconvertible under physiological conditions to the corresponding freecarboxylic acid. Most preferred prodrug esters are the C₁ -C₇ alkyl, C₆aryl-C₁ -C₇ alkyl, C₁ -C₇ alkanoyloxymethyl, C₁ -C₇ alkylamino-straightchain C₂ -C₄ -alkyl esters for example 2-diethylaminoethyl.

The pharmaceutically acceptable salts are the alkali metal salts (sodiumor potassium), the alkaline earth metal salts (calcium or magnesium), orammonium salts derived from ammonia or from pharmaceutically acceptableorganic amines, for example C₁ -C₇ alkylamine, cyclohexylamine,triethanolamine, ethylenediamine or tris-(hydroxymethyl)-aminomethane.The compounds of the invention which are basic amines form acid additionsalts of preferably pharmaceutically acceptable inorganic or organicacids for example hydrohalic, sulfuric, phosphoric acid or aliphatic oraromatic carboxylic or sulfonic acid, for example acetic, succinic,lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,p-toluensulfonic or naphthalenesulfonic acid.

The most preferred compounds according to the invention known at presentare

(R)-α-Amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid;

(R)-α-Amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;and

(R)-α-Amino-6,7-diethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid.

Preparations

The compounds of the present invention can be prepared by methods knownin the art using readily available or readily prepared startingmaterials, for example several synthetic routes depending on thesubstituents of the quinoline starting material, are listed in thefollowing. The substituted quinoline (III), which is a starting compound##STR4## can be prepared by the Doebner-von Miller variation of theSkraup quinoline synthesis, that is from a suitably substituted orunsubstituted aniline and trans-2-methyl butenal. After brominating withN-bromosuccinimide the bromomethyl group is reacted with a trialkylphosphite under Arbuzov reaction conditions. After a second brominationwith N-bromosuccinimide the bromomethyl group is used to C-alkylate adialkyl acetamidomalonate in the presence of an alkali metal alkoxide.Alternatively alkylation may be accomplished with a N-benzylideneglycine ester in the presence of an alkali metal alkoxide or underphase-transfer conditions using a chiral phase-transfer catalystyielding an enantiomerically pure product. The compounds that appear asracemic mixtures can be readily resolved into their pure enantiomers byconventional means. The compounds of the invention are then obtained byremoval of the protecting groups.

The substituted quinoline (IV) ##STR5## can be prepared by a modifiedFriedlander quinoline synthesis, that is by condensing a suitablysubstituted or unsubstituted o-nitro benzaldehyde with ethylacetoacetate and subsequent reduction of the nitro group. Afterbromination with N-bromosuccinimide the bromomethyl group is used toC-alkylate a dialkyl acetamidomalonate in the presence of an alkalimetal alkoxide. Alternatively alkylation may be accomplished with aN-benzylidene glycine ester in the presence of an alkali metal alkoxideor under phase-transfer conditions using a chiral phase-transfercatalyst yielding an enantiomerically pure product. The ethyl3-quinolincarboxylate can then directly or indirectly be reduced to ahydroxymethyl group. After bromination with phosphorus tribromide thebromomethyl group is reacted with a trialkyl phosphite under Arbuzovreaction conditions yielding the desired phosphonate. The compounds thatappear as racemic mixtures can be readily resolved into their pureenantiomers by conventional means. The compounds of the invention arethen obtained by removal of the protecting groups.

The substituted quinoline (V) ##STR6## can be prepared in many ways forexample, by lithiating a 2-chloroquinoline at C-3 with a lithiumdialkylamide, trapping with formaldehyde and subsequent bromination withphosphorus tribromide or by first transforming a3-carboxyethyl-2-quinolone to its 2-haloderivative subsequent reductionof the 3-carboxy group and finally bromination with phosphorustribromide will yield the 2-bromo-3-bromomethylquinoline (V). Thebromomethyl group is reacted with a trialkyl phosphite under Arbuzovreaction conditions to yield the desired phosphonate. The2-bromoquinoline is then coupled with a 2-amidoacrylate under modifiedHeck reaction conditions, or reacted with a metallated β-iodoalanine.The didehydroamino acid derivative is catalytically hydrogenated using anoble metal catalyst for example Pd/C or a an asymmetric catalystyielding an enantiomerically pure product. The compounds that appear asracemic mixtures can be readily resolved into their pure enantiomers byconventional means. The compounds of the invention are then obtained byremoval of the protecting groups.

The preparation of the compounds according to the invention will now bedescribed in detail.

A compound of the formula (VI) ##STR7## is reacted with a suitablyprotected glycine anion equivalent to yield a compound of the formula Iwith protecting groups whereafter the protecting groups are removed; or

a protected compound of the formula (VII) ##STR8## is reacted with atrialkyl phosphite, whereafter the protecting groups are removed, or acompound of the formula (VIII) ##STR9## is reacted with a suitablyprotected 2-amidoacrylate, the compound formed is hydrogenated and theprotecting groups are removed, or (VIII) is reacted with a suitablyprotected metallated β-iodoalanine wherafter the protecting groups areremoved.

EXAMPLES

The invention will now be described in more detail with the followingexamples which are not to be construed as limiting the invention.

Example 1 α-Amino-3-(phosphonomethyl)-2-quinolinepropanoic acid

To a solution of 2,3-dimethylquinoline (0.50 g, 3.2 mmol) in carbontetrachloride (40 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide(1.14 g, 6.4 mmol) were added. The reaction mixture was refluxed for 4hours, and then cooled to room temperature. The precipitate was removedby filtration and the filtrate was evaporated in vacuo. The residue wasflash chromatographed on silica gel with ethyl acetate/petroleum etheras the eluent to give 0.25 g of 3-bromomethyl-2-methylquinoline.

A mixture of the obtained 3-bromomethyl-2-methylquinoline (0.25 g, 1.0mmol) and trimethyl phosphite (0.4 ml, 3.2 mmol) was refluxed in toluene(10 ml) for 16 hours. The reaction mixture was then concentrated invacuo and the residue was flash chromatographed on silica gel. Elutionwith ethyl acetate afforded 0.28 g of3-(dimethylphosphonomethyl)-2-methylquinoline.

A solution of the obtained 3-(dimethylphosphonomethyl)-2-methylquinoline(0.28 g, 1.0 mmol) in carbon tetrachloride (20 ml) was treated withbenzoylperoxide (50 mg) followed by N-bromosuccinimide (0.20 g, 1.1mmol). The reaction mixture was refluxed for 4 hours, filtered andconcentrated in vacuo. The residue was flash chromatographed on silicagel with ethyl acetate as the eluent to give 0.21 g of2-bromomethyl-3-(dimethylphosphonomethyl)quinoline.

To a mixture of sodium (15 mg, 0.65 mmol) in ethanol (5 ml) diethylacetamidomalonate (0.133 g, 0.61 mmol) was added. After stirring for 15minutes 2-bromomethyl-3-(dimethylphosphonomethyl)quinoline (0.21 g, 0.61mmol) dissolved in ethanol (5 ml) was added. The reaction mixture wasstirred under dry nitrogen at room temperature for 3 hours. Ethylacetate (25 ml) and water (5 ml) were added to the reaction mixture. Theorganic layer was separated and the water layer was washed with ethylacetate (10 ml). The combined organic extracts were dried over sodiumsulphate, filtered and evaporated in vacuo. The residue was flashchromatographed on silica gel. Elution with ethyl acetate afforded 0.11g of α-acetylamino-(3-dimethylphosphonomethyl)-2-quinolinepropandioicacid diethyl ester.

The intermediate acetylamino derivative (0.11 g, 0.23 mmol) was refluxedin 6N hydrochloric acid (10 ml) for 3 hours. The mixture wasconcentrated in vacuo and then eluted through Dowex 50W*8H first withwater and then with 1M NH₃ to afford 50 mg ofα-amino-3-(phosphonomethyl)-2-quinolinepropanoic acid ammonium salt. ¹ HNMR (D₂ O, 400 MHz): δ 3.30 (d, 2H, CH₂ --P), 3.71 (d, 2H, CH₂), 4.49(m, 1H, CH), 7.4-8.2 (m, 5H, ArH).

Example 2 α-Amino-2-(phosphonomethyl)-3-quinolinepropanoic acid

To a solution of 2,3-dimethylquinoline (1.0 g, 6.4 mmol) in carbontetrachloride (60 ml) benzoyl peroxide (100 mg) and N-bromosuccinimide(2.28 g, 12.8 mmol) were added. The reaction mixture was refluxed for 4hours, and then cooled to room temperature. The precipitate was removedby filtration and the filtrate was evaporated in vacuo. The residue wasflash chromatographed on silica gel with ethyl acetate/petroleum etheras the eluent to give 0.50 g of 2,3-di(bromomethyl)quinoline.

A mixture of 2,3-di(bromomethyl)quinoline (0.50 g, 1.4 mmol) andtrimethyl phosphite (0.18 ml, 1.4 mmol) was refluxed in toluene for 4hours. The reaction mixture was then concentrated in vacuo and theresidue was flash chromatographed on silica gel. Elution with ethylacetate afforded 0.35 g of3-bromomethyl-2-(dimethylphosphonomethyl)quinoline.

To a mixture of sodium (20 mg, 0.90 mmol) in ethanol (5 ml) diethylacetamidomalonate (0.19 g, 0.87 mmol) was added. After stirring for 15minutes 3-bromomethyl-2-(dimethylphosphonomethyl)quinoline (0.30 g, 0.87mmol) dissolved in ethanol (5 ml) was added. The reaction mixture wasstirred under dry nitrogen at room temperature for 3 hours. Ethylacetate (25 ml) and water (5 ml) were added to the reaction mixture. Theorganic layer was separated and the water layer was washed with ethylacetate (10 ml). The combined organic extracts were dried over sodiumsulphate, filtered and evaporated in vacuo. The residue was flashchromatographed on silica gel. Elution with ethyl acetate afforded 0.30g of α-acetylamino-(2-dimethylphosphonomethyl)-3-quinolinepropandioicacid diethyl ester.

The intermediate acetylamino derivative (0.25 g, 0.52 mmol) was refluxedin 6N hydrochloric acid (10 ml) for 6 hours. The mixture wasconcentrated in vacuo and 90 mg ofα-amino-2-(phosphonomethyl)-3-quinolinepropanoic acid was precipitatedfrom water. ¹ H NMR (D₂ O, 400 MHz): δ 3.41 (d, 2H, CH₂), 3.60 (d, 2H,CH₂ --P), 4.49 (m, 1H, CH), 7.4-8.7 (m, 5H, ArH).

Example 3 α-Amino-6-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid

To a solution of 6-chloro-2,3-dimethylquinoline (2.0 g, 10.5 mmol) incarbon tetrachloride (80 ml) benzoyl peroxide (100 mg) andN-bromosuccinimide (3.7 g, 21.0 mmol) were added. The reaction mixturewas refluxed for 4 hours, and then cooled to room temperature. Theprecipitate was removed by filtration and the filtrate was evaporated invacuo. The residue was flash chromatographed on silica gel with ethylacetate/petroleum ether as the eluent to give 0.90 g3-bromomethyl-6-chloro-2-methylquinoline.

A mixture of 3-bromomethyl-6-chloro-2-methylquinoline (0.85 g, 3.0 mmol)and trimethyl phosphite (1.2 ml, 9.6 mmol) was refluxed in toluene (20ml) for 16 hours. The reaction mixture was then concentrated in vacuoand the residue was flash chromatographed on silica gel. Elution withethyl acetate afforded 0.90 g of6-chloro-3-(dimethylphosphonomethyl)-2-methylquinoline.

A solution of 6-chloro-3-(dimethylphosphonomethyl)-2-methylquinoline(0.85 g, 2.7 mmol) in carbon tetrachloride (40 ml) was treated withbenzoyl peroxide (100 mg) followed by N-bromosuccinimide (0.50 g, 2.8mmol). The reaction mixture was refluxed for 4 hours, filtered andconcentrated in vacuo. The residue was flash chromatographed on silicagel with ethyl acetate as the eluent to give 0.75 g of2-bromomethyl-6-chloro-3-(dimethylphosphonomethyl)quinoline.

To a mixture of sodium (44 mg, 1.9 mmol) in ethanol (10 ml) diethylacetamidomalonate (0.40 g, 1.85 mmol) was added. After stirring for 15minutes 2-bromomethyl-6-chloro-3-(dimethylphosphonomethyl)quinoline(0.70 g, 1.85 mmol) dissolved in ethanol (10 ml) was added. The reactionmixture was stirred under dry nitrogen at room temperature for 3 hours.Ethylacetate (50 ml) and water (10 ml) were added to the reactionmixture. The organic layer was separated and the water layer was washedwith ethyl acetate (20 ml). The combined organic extracts were driedover sodium sulphate, filtered and evaporated in vacuo. The residue wasflash chromatographed on silica gel. Elution with ethyl acetate afforded0.46 g ofα-acetylamino-6-chloro-(3-dimethylphosphonomethyl)-2-quinolinepropandioicacid diethyl ester.

The intermediate acetylamino derivative (0.40 g, 78 mmol) was refluxedin 6N hydrochloric acid for 6 hours. The mixture was concentrated invacuo and 150 mg ofα-amino-6-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid wasprecipitated from water. ¹ H NMR (D₂ O, 400 MHz): δ 3.29 (d, 2H, CH₂--P), 3.69 (d, 2H, CH₂), 4.49 (m, 1H, CH), 7.4-8.7 (m, 4H, ArH).

Example 4 (R)-α-Amino-7-ethoxy-3-(phosphonomethyl)-2-quinolinepropanoicacid

Phosphorus oxychloride (36.4 ml, 0.4 mol) was slowly added to stirredice-cooled dimethylformamide (6.6 ml, 86 mmol). The cooling-bath wasremoved and N-(3-ethoxyphenyl)-3 chloropropionamide (13 g, 57 mmol) wasadded to the mixture which then was heated at reflux for 10 h. Aftercooling the mixture was poured onto crusched ice and solid sodiumcarbonate was added until ceasure of evolution of carbon dioxide. Themixture was extracted with toluene-EtOAc, after drying (sodium sulfate)the extract was filtered through a pad of silica gel and the solventswere evaporated giving 9.9 g of2-chloro-3-chloromethyl-7-ethoxyquinoline (about 85% pure).Recrystallization from propyl acetate gave 6.0 g of pure material.

The product from the above reaction was allowed to react with 15 ml oftriethyl phosphite at 125° C. for 15 h. The triethyl phosphite wasevaporated under vacuum at 60° C. Recrystallization of the residue gave2-chloro-3-diethylphosponomethyl-7-ethoxyquinoline.

The above phosphonate was treated for 10 h with 5 equivalents of sodiumiodide in refluxing 2-butanone in the presence of 0.5 equivalents ofmethanesulfonic acid. The mixture was neutralized with saturated sodiumhydrogen carbonate and extracted with ether. Evaporation of solventsgave 3-diethylphosphonomethyl-7-ethoxy-2-iodoquinoline which stillcontained about 20% of the starting chloride.

The above iodide was used in the coupling with the zinc reagent derivedfrom BOC-protected methyl ester of D-3-iodoalanine as described in thefollowing. The zinc reagent was generated in a mixture of toluene andN,N-dimethylacetamide essentially as described in Jackson et al., J.Org. Chem. 1992, 57, 3397. To the solution of the zinc reagent wereadded tri-o-tolylphosphine (0.2 equiv.), palladium chloride (0.1 equiv.)and the above iodide (0.55 equiv.) and sonication was continued for 3 h.The mixture was worked-up by partitioning between water and ethylacetate. Evaporation of solvents gave methylα-t-butoxycarbonylamino-3-diethylphosphonomethyl-7-ethoxy-2-quinolinepropionatein 50% yield after chromatography.

Deprotection of the amino acid was effected in refluxing 6M HCl for 6 h.Evaporation of the solvent gave a residue which was put onto an acidicion-exchange resin and eluted with water. Collection ofninhydrin-sensitive fractions and evaporation of solvent gave(R)-α-amino-3-phosphonomethyl-7-ethoxy-2-quinolinepropanoic acid. ¹³C-NMR (D₂ O plus NH₃ vapours): δ (ppm) 174.7, 158.7, 156.3, 146.3,138.0, 137.9, 128.6, 122.6, 118.8, 106.2, 64.4, 54.1, 34.2, 34.0, 32.8,13.9.

Example 5(R)-α-Amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid

2-Chloro-3-diethylphosphonomethyl-6,7-dimethylquinoline (0.40 g, 1.17mmol), prepared as described in Example 4 was dissolved in 2-butanone(20 ml) and treated with sodium iodide (0.39 g, 2.6 mmol) andp-toluenesulfonic acid (0.11 g, 0.58 mmol). The mixture was refluxed for10 hours. Ethyl acetate and saturated sodium hydrogen carbonate wereadded. The organic phase was separated and filtered through a pad ofsilica gel. Evaporation of solvents gave 0.28 g of3-diethylphosphonomethyl-6,7-dimethyl-2-iodoquinoline.

A solution of methyl (R)-α-t-butoxycarbonylamino-β-iodopropionate (0.40g, 1.21 mmol) in dry toluene (6 ml) and dry dimethylacetamide (0.4 ml)was added to a nitrogen purged flask charged with zinc-copper couple(0.16 g, 2.43 mmol). The resulting mixture was sonicated under nitrogenfor 55 minutes until no starting material remained. Palladium chloride(23 mg, 0.13 mmol) and tri-o-tolylphosphine (61 mg, 0.20 mmol) wereadded followed by the above prepared 2-iodoquinoline (0.28 g, 0.65 mmol)dissolved in toluene (2 ml). The mixture was sonicated one hour and thenstirred at 55° C. for 3 hours. Ethyl acetate and saturated sodiumhydrogen carbonate were added. The organic phase was washed with waterand evaporated. Flash chromatography over silica gel gave 0.23 g ofmethyl(R)-α-t-butoxycarbonylamino-3-diethylphosphonomethyl-6,7-dimethyl-2-quinolinepropionate.

The above amino acid derivative (0.23 g, 0.45 mmol) was refluxed in 6Nhydrochloric acid (10 ml) for 6 hours. The mixture was concentrated invacuo and 110 mg of(R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acidwas precipitated from water. ¹ H NMR (D₂ O plus NH₃, 400 MHz): δ 2.28(s, 3H, CH₃), 2.30 (s, 3H, CH₃), 3.00 (m, 2H, CH₂ --P), 3.45 (m, 2H,CH₂), 4.20 (m, 1H, CH), 7.44 (s, 1H, ArH), 7.60 (s, 1H, ArH), 7.92 (d,1H, ArH).

Example 6 (R)-α-Amino-7-chloro-3-(phosphonomethyl)-2-quinolinepropanoicacid

Methyl(R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-2-quinolinepropionate(0.23 g, 0.45 mmol), prepared as described in example 5, was refluxed in6N hydrochloric acid (10 ml) for 6 hours. The mixture was concentratedin vacuo and 100 mg of(R)-α-amino-7-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid wasprecipitated from water. ¹ H NMR(D₂ O, 400 MHz): δ 3.18 (d, 2H, CH₂--P), 3.58 (m, 2H, CH₂), 4.38 (m, 1H, CH), 7.12 (d, 1H, ArH), 7.47 (d,1H, ArH), 7.53 (s, 1H, ArH), 8.42 (d, 1H, ArH).

Example 7 α-Amino-6,7-dimethoxy-3-(phosphonomethyl)-2-quinolinepropanoicacid

A mixture of 2-nitro-4,5-dimethoxybenzaldehyde (5.28 g, 25 mmol) andRaney-nickel in THF (100 ml) was hydrogenated until three equivalents ofhydrogen had been consumed. The mixture was filtered through Celite.Ethyl acetoacetate (3.2 ml, 25 mmol) and piperidine (12 drops) wereadded and the solution was refluxed for 4 h and concentrated. The solidresidue was recrystallized from MeOH to give 3.89 g ethyl6,7-dimethoxy-2-methylquinoline-3-carboxylic acid.

A solution of 6,7-dimethoxy-2-methylquinoline-3-carboxylic acid ethylester (2.83 g, 10.3 mmol) in dry THF (75 ml) was added dropwise over 20min to a stirred, ice-cooled suspension of lithium aluminiumhydride(0.39 g, 10.3 mmol) in dry THF (50 ml). The mixture was allowed to cometo room temperature over 2 h and the excess lithium aluminiumhydride wasdecomposed by sequential careful addition of ethyl acetate, acetone and2M NaOH. The mixture was filtered and the white gummy material wasextracted twice with acetone. The filtrate and the extracts werecombined and concentrated to give 2.31 g of6,7-dimethoxy-2-methylquinoline-3-methanol.

6,7-Dimethoxy-2-methylquinoline-3-methanol (2.31 g, 9.9 mmol) wasdissolved in thionylchloride (50 ml) and refluxed for 2 h. The solutionwas concentrated and the residue partitioned between ethyl acetate andaqeous NaHCO₃. The layers were separated and the aqeous phase extractedwith ethyl acetate. The combined organic phases were washed with waterand brine and dried over MgSO₄. Evaporation of the solvent gave 2.48 g6,7-dimethoxy-3-chloromethyl-2-methylquinoline.

A mixture of 6,7-dimethoxy-3-chloromethyl-2-methylquinoline (2.48 g, 9.9mmol) and triethylphosphite (6 ml) was heated at 160° C. for 4 h andcooled to room temperature. Excess triethylphosphite was removed byextraction with hexane and the remaining dark oil was purified bychromatography to give 3.50 g3-(diethylphosphonomethyl)-6,7-dimethoxy-2-methylquinoline.

SeO₂ (0.56 g, 5.06 mmol) was added to a solution of3-(diethylphosphonomethyl)-6,7-dimethoxy-2-methylquinoline (1.79 g, 5.06mmol) in dioxane (25 ml). The mixture was refluxed for 75 min, filteredand concentrated. The remaining oil was purified by chromatography togive 1.48 g3-(diethylphosphonomethyl)-6,7-dimethoxyquinoline-2-carboxaldehyde.

A solution of N-benzyloxycarbonyl-α-(dimethylphosphonyl)glycin methylester (0.99 g, 3 mmol) in THF (4 ml) was added dropwise to a stirredsuspension of NaH (82 mg, 3.4 mmol) in THF (2 ml) at room temperature.After the gas evolution had ceased a solution of3-(diethylphosphonomethyl)-6,7-dimethoxyquinoline-2-carboxaldehyde (1.13g, 3 mmol) in THF (3 ml) was added dropwise over 2 min. After 2 h thereaction was quenched with aqeous NH₄ Cl and partitioned between ethylacetate and water. The layers were separated and the aqeous phaseextracted with ethyl acetate. The combined organic phases were washedwith water and brine and dried over MgSO₄. Concentration gave a brownfoam which was purified by chromatography to give 1.04 gα-(benzyloxycarbonylamino)-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolineacrylicacid methyl ester.

A mixture ofα-(benzyloxycarbonylamino)-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolineacrylicacid methyl ester (0.14 g, 0.25 mmol) and a catalytic amount ofpalladium on charcoal (10%) in MeOH (10 ml) was hydrogenated at 4 barfor 20 h. Filtration and chromatographic purification gave 0.09 gα-amino-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolinepropanoicacid methyl ester.

α-Amino-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolinepropanoicacid methyl ester (0.09 g, 0.2 mmol) was refluxed in 6M HCl (15 ml) for6 h. The mixture was concentrated and dissolved in water. After removalof some undissolved material by filtration, 38 mg of the title compound,α-amino-6,7-dimethoxy-3-(phosphonomethyl)-2-quinolinepropanoic acid wasprecipitated by addition of acetonitrile. ¹ H NMR(D₂ O, 400 MHz: δ 3.22(dd, 2H), 3.66 (m, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 4.15 (m, 1H), 7.22(s, 1H), 7.37 (s, 1H), 8.53 (s, 1H).

Example 8 (R)-α-Amino-7-methyl-3-(phosphonomethyl)-2-quinolinepropanoicacid hydrochloride

To a solution of 30 ml m-toluidine in 150 ml toluene was added asolution of 25 ml of acetyl chloride in 50 ml of toluene. The reactionmixture was cooled in a +20° C. water bath giving a reaction oftemperature of +50° C. at the end of the addition. The mixture wasstirred at room temperature overnight, then diluted with 100 ml oftoluene, washed with 200 ml of H₂ O, 100 ml of saturated sodiumbicarbonate solution and then filtered through phase separating paperand evaporated in vacuo to give 37.2 g of N-acetamido-m-toluidine as acrystalline mass.

31 ml (0.4 mol) of dry dimethylformamide was cooled in anice/ethanol-bath, and 87 ml (0.94 mol) of phosphorous oxychloride wasadded during 30 minutes with mechanical stirring to give the formiminiumchloride as a suspension. 20 g (0.134 mol) of powderedN-acetamido-m-toluidine was then added at 0° to +5° C. The mixture wasallowed to reach room temperature over 1.5 hours and was then heated at+80° C. in a stoppered flask fitted with a reflux condenser for 3 hours.After standing at room temperature overnight the mixture was poured onto1 l of chrushed ice and the mixture stirred for approx. 30 minutes. Theprecipitate was filtered off, washed with water and dried in vacuo togive 18.5 g of 2-chloro-3-formyl-7-methylquinoline.

To a stirred solution of 6.9 g (180 mmol) of sodium borohydride in 250ml of absolute ethanol, a solution of 15 g (73 mmol) of2-chloro-3-formyl-7-methylquinoline in 250 ml of dry tetrahydrofuran wasadded over 15 minutes without cooling. During the addition a slight H₂-evolution and a temperature rise to +28° C. was observed. The reactionmixture was stirred at room temperature for 4 hours and then 4 ml of thereaction mixture was evaporated in vacuo and the residue dissolved inethyl acetate, extracted with saturated sodium hydrogen carbonatesolution, dried over sodium sulfate and evaporated in vacuo to give aresidue of 100 mg. ¹ H-NMR indicated complete conversion to the alcohol.After 5 hours the whole reaction mixture was worked up in the same wayto give 14.8 g 2-chloro-3-hydroxymethyl-7-methylquinoline afterevaporation.

10 ml (106 mmol) of phosphorus tribromide was cooled in an ice-bath and6.4 g (30.8 mmol) of solid 2-chloro-3-hydroxymethyl-7-methylquinolinewas added with stirring. The temperature reached +10° C. at the end ofthe addition and a thick suspension was formed. The cooling bath wasthen removed and the mixture was heated at +100° C. for 3 hours. 50 mlof toluene was added and the mixture refluxed for another 3 hours. Thereaction mixture was then poured onto 200 ml of ice, the resultingmixture filtered, the toluene phase separated from the filtrate, thesolids redissolved in methylene chloride, the toluene and methylenechloride solutions combined, washed with water, dried and avaporated invacuo to give 5.9 g of 2-bromo-3-bromomethyl-7-methylquinoline as acrystalline solid. ¹ H-, ¹³ C-NMR and MS showed the presence of 20%2-chloro-3-bromomethyl-7-methylquinoline as an impurity which could notbe removed by recrystallization.

To a solution of 4 g (12.6 mmol) of the above2-bromo-3-bromomethyl-7-methylquinoline in 50 ml of toluene was added4.3 ml (25 mmol) of triethyl phosphite and the mixture was refluxed for22 hours. Evaporation in vacuo gave 5.1 g of a solid residue which wasdissolved in 10 ml of toluene (slightly warmed) and diluted with hexaneuntil turbid. The solution was decanted from a small amount of a fluffyprecipitate and was then allowed to crystallize in an ice bath. Thecrystalline precipitate was filtered off, washed with hexane and driedin vacuo to give 3.3 g of2-bromo-3-diethylphosphonomethyl-7-methylquinoline containing 20% of2-chloro-3-diethylphosphonomethyl-7-methylquinoline as an impurity.

To a solution of 2.5 g (7.5 mmol) of N-t-butoxycarbonyl-3-iodo-D-alaninemethyl ester in 30 ml of dry toluene and 2 ml of dryN,N-dimethylacetamide was added 900 mg of Zn(Cu) dust. The mixture wastreated in an ultrasonic bath for 1 hour 50 minutes after which time TLCindicated complete conversion of the iodo-alanine derivative. A mixtureof 70 mg (0.4 mmol) of PdCl₂ and 240 mg (0.8 mmol) oftri-o-tolylphosphine was added followed by 1.9 g (5.0 mmol) of2-bromo-3-diethylphosphonomethyl-7-methylquinoline and sonication wascontinued for 3 hours at 50°-60° C. and the mixture was then allowed tostand at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate, extracted with saturated sodium hydrogen carbonatesolution, dried over sodium sulfate and evaporated to give 3.91 g of anoil. The crude product was subjected to chromatography on silica gelwith ethyl acetate as an eluant to give 1.334 g of pure methyl(R)-α-t-butoxycarbonylamino-3-didiethylphosphonomethyl-7-methyl-2-quinolinepropionate.

1.27 g (2.57 mmol) of methyl(R)-α-t-butoxycarbonylamino-3-diethylphosphonomethyl-7-methyl-2-quinolinepropionatewas added to 20 ml of 6M hydrochloric acid and the mixture was refluxedfor 6 hours. Evaporation in vacuo gave 1.03 g of a solid which wasredissolved in 5 ml of water, 5 ml of isopropyl alcohol was added andthe mixture was allowed to crystallize in an ice-bath. The precipitatewas filtered off and dried in vacuo to give 399 mg ofα-amino-3-phosphonomethyl-7-methyl-2-quinolinepropanoic acidhydrochloride. ¹³ C-NMR(D₂ O): δ (ppm) 21.5, 30.7, 31.9, 32.0, 51.6,118.1, 126.2, 127.9, 128.6, 132.4, 137.4, 140.4, 147.4, 151.4, 170.8.

Example 9(R)-α-Amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid

3,4-Dichloro-6-nitrobenzaldehyde (4.40 g, 20 mmol) was dissolved in 50%aqueous ethanol (200 ml) at 50°-60° C. and the solution was added to asolution of iron(II) sulfate heptahydrate (27.8 g, 100 mmol) in water(200 ml) at 90° C. Concentrated (25%) aqueous ammonia (50 ml) was addedin several portions with intensive stirring while the temperature waskept close to the boiling point. The mixture was refluxed for 5-10 min.and cooled. The precipitate was filtered off and washed with ethanol.The filtrate was concentrated in vacuo until most of the ethanol wasremoved. The resulting precipitate was collected, washed with water anddried in vacuo at 40°-50° C. to give 3.3 g of3,4-dichloro-6-aminobenzaldehyde.

3,4-Dichloro-6-aminobenzaldehyde (2.85 g, 15 mmol) was stirred withdimethylmalonate (10 ml) at 140° C. for 20 h. The mixture was dilutedwith ethyl ether (100 ml). The precipitate was collected, washed twicewith ethyl ether and dried in vacuo to give 2.86 g of methyl6,7-dichloro-2-hydroxyquinoline-3-carboxylate.

Methyl 6,7-dichloro-2-hydroxyquinoline-3-carboxylate (2.72 g, 10 mmol)was added in small portions to a stirred solution of DIBAL (1M inhexane, 25 ml, 25 mmol) in tetrahydrofuran (25 ml) under nitrogen at25°-30° C. The mixture was stirred at ambient temperature for 0.5 h andthen quenched with an excess of 20% HCl at 5°-10° C. The precipitate wascollected and washed with water, tetrahydrofuran and ethyl ether to give2.12 g of 6,7-dichloro-2-hydroxyquinoline-3-methanol.

A mixture of 6,7-dichloro-2-hydroxyquinoline-3-methanol (1.22 g, 5 mmol)and phosphorus oxybromide (5 g) was stirred at 110° C. for 2-3 h. Aftercooling it was cautiously quenched with water keeping the temperaturebelow 50° C. The precipitate was collected and washed with water,acetonitrile and ethyl ether to give 1.66 g of6,7-dichloro-2-bromo-3-bromomethylquinoline.

A mixture of 6,7-dichloro-2-bromo-3-bromomethylquinoline (0.74 g, 2mmol) and trimethylphosphite (5 ml) was heated at 80°-90° C. for 2-3h.Then the excess trimethylphosphite was removed in vacuo at 70°-80° C.and the oily residue was made crystalline by treating with hexane-ethylether (1:1). The crystalls were collected, washed with toluene and driedin vacuo to give 0.65 g of6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline.

A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.66 g,2 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml) wasadded to a zinc-copper couple (0.31 g). The resulted mixture wassonicated at 40°-45° C. under nitrogen for 2.5-3 h until no startingmaterial remained (as judged by TLC). Tri-o-tolylphosphine (0.06 g, 0.2mmol) and palladium chloride (0.02 g, 0.1 mmol) were added followed by asolution of 6,7-dichloro-3-dimethylphosphonomethyl-2-bromoquinoline (0.4g, 1 mmol) in dry benzene (3 ml) and dry dimethylacetamide (0.5 ml). Theresulted mixture was stirred under nitrogen at 50°-60° C. for 2.5-3 hand then allowed to cool. Water was added and the mixture was filteredthrough Celite, the latter was washed with ethyl acetate. The combinedorganic phases were separated, dried, (MgSO₄) and concentrated in vacuo.The residue was coevaporated several times with toluene to remove mostof the dimethylacetamide and then purified on a silica gel column using0-2% methanol in chloroform as eluent to give 0.33 g of methyl(R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate.

Methyl(R)-α-t-butoxycarbonylamino-6,7-dichloro-3-dimethylphosphonomethyl-2-quinolinepropionate(0.26 g, 0.5 mmol) was refluxed in 6M HCl (20 ml) for 4 h. The solventwas removed in vacuo and the residue was coevaporated 3 times withacetonitrile. The resulting powder was treated with water andchloroform, filtered off and finally recrystallized from methanol togive 0.11 g of(R)-α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid.¹ H NMR (D₂ O, 400 MHz): δ 3.15 (d,2H), 3.56 (dd,1H), 3.64 (dd,1H), 4.41(m,1H), 7.91 (s,1H), 8.00 (s,1H), 8.02 (s,1H).

Example 10 (R)-α-Amino-5-chloro-3-(phosphonomethyl)-2-quinolinepropanoicacid

Following the procedure of Example 9 starting with2-chloro-6-nitrobenzaldehyde, the title compound was prepared. ¹ H NMR(CD₃ OD, 400 MHz): δ 3.52 (d,2H), 3.94 (m,2H), 4.76 (m,1H), 7.78 (m,1H),8.12 (m,2H), 8.76 (d,1H).

Example 11 (R)-α-Amino-6-fluoro-3-(phosphonomethyl)-2 quinolinepropanoicacid

Following the procedure of Example 9 starting with3-fluoro-6-nitrobenzaldehyde, the title compound was prepared. ¹ H NMR(D₂ O, 400 MHz): δ 3.24 (d,2H), 3.71 (m,2H), 4.43 (t,1H), 7.60 (m,2H),7.94 (m,1H), 8.61 (d,1H).

Example 12 (R)-α-Amino-6,8-dichloro-3-(phosphonomethyl)-2quinolinepropanoic acid

Following the procedure of example 9 starting with3,5-dichloro-6-nitrobenzaldehyde, the title compound was prepared. ¹ HNMR (D₂ O, 400 MHz): δ 3.15 (dd,2H), 3.70 (m,2H), 4.55 (t,1H), 7.36(s,1H), 7.44 (s,1H), 7.80 (m,1H).

Example 13(R)-α-Amino-7-chloro-6-methyl-3-(phosphonomethyl)-quinolinepropanoicacid

3-Chloromethyl-2,7-dichloro-6-methylquinoline was prepared following theprocedure of Example 4 starting with3-chloro-N-(3-chloro-4-methylphenyl)propionamide.

3-Chloromethyl-2,7-dichloro-6-methylquinoline (3.4 g, 13 mmol) andphosphorus oxybromide (15 g) was heated to 100° C. for 4 h. The mixturewas allowed to cool and then poured onto crushed ice. The resultingmixture was extracted with methylene chloride and the organic phase waswashed with saturated sodium hydrogen carbonate solution, dried overMgSO₄ and evaporated in vacuo to yield 4.4 g of2-bromo-3-bromomethyl-7-chloro-6-methylquinoline.

A mixture of 2-bromo-3-bromomethyl-7-chloro-6-methylquinoline (4.2 g, 12mmol), toluene (50 ml) and triethylphosphite (4.2 ml) was refluxed for20 h. After cooling the solution was concentrated in vacuum and theproduct precipitated by the addition of hexane. The crystals werefiltered off, washed with hexane and dried in vacuo to give 4.5 g of2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline.

A solution of N-t-butoxycarbonyl-3-iodo-D-alanine methyl ester (0.81 g,2.46 mmol) in dry toluene (12 ml) and dry dimethylacetamide (0.8 ml) wasadded to a nitrogen purged flask charged with zink-copper couple (0.32g, 4.92 mmol). The mixture was treated in an ultrasonic bath for 1 huntil no starting material remained (as judged by TLC). A mixture ofPdCl₂ (23 mg, 0.13 mmol) and tri-o-tolylphosphine (79 mg, 0.26 mmol) wasadded followed by2-bromo-7-chloro-3-diethylphosphonomethyl-6-methylquinoline (0.5 g, 1.23mmol) and sonication was continued for 3 hours at 50°-60° C. Aftercooling the reaction mixture was diluted with ethyl acetate, extractedwith saturated sodium hydrogen carbonate solution, dried over MgSO₄ andevaporated. The crude product was subjected to chromatography on silicagel with ethyl acetate as eluant to yield 0.49 g of methyl(R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-6-methyl-2-quinolinepropionate.

(R)-α-t-butoxycarbonylamino-7-chloro-3-diethylphosphonomethyl-6-methyl-2-quinolinepropionatewas refluxed in 6N hydrochloric acid (15 ml) for 6 hours. The mixturewas concentrated in vacuo and the product was crystallized from awater-acetone mixture. The product was filtered off and dried in vacuoto yield 0.31 g of(R)-α-7-chloro-6-methyl-3-(phosphonomethyl)-2-quinolinepropanoic acid. ¹H NMR (D₂ O, 400 MHz): δ 2.10 (s,3H), 3.26 (d,2H), 3.63 (m,2H), 4.44(t,1H), 7.61 (s,1H), 7.75 (s,1H), 8.53 (d,1H).

Example 14 (R)-α-Amino-6,7-diethyl-3-(phosphonomethyl)-2quinolinepropanoic acid

Following the procedure of Example 8 starting withN-(3,4-diethylphenyl)acetamide, the title compound was prepared. ¹ H NMR(D₂ O, 400 MHz): δ 1.10 (m,6H), 2.69 (m,4H), 3.36 (d,2H), 3.6 (d,2H),4.54 (t,1H), 7.73 (s,1H), 7.77 (s,1H), 8.69 (s,1H).

Example 15 (S)-α-Amino-6,7-dimethyl-3-(phosphonomethyl)-2quinolinepropanoic acid

Following the procedure of Example 13 starting with3-chloro-N-(3,4-dimethylphenyl)propionamide and usingN-t-butoxycarbonyl-3-iodo-L-alanine methyl ester in the couplingreaction, the title compound was prepared. ¹ H NMR (D₂ O, 400 MHz): δ2.10 (s, 3H), 2.12 (s,3H), 3.23 (d,2H), 3.62 (d,2H), 4.45 (t,1H), 7.58(s,1H), 7.62 (s,1H), 8.49 (d,1H).

Example 16 Ethyl (R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2quinolinepropionate

Following the procedure of Example 13 starting with3-chloro-N-(3,4-dimethylphenyl)propionamide, the(R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2 quinolinepropanoic acidwas prepared. This amino acid (0.15 g, 0.44 mmol) was refluxed inethanol (15 ml) saturated with hydrochloric acid for 16 hours. Thesolvent was removed in vacuo and the product was recrystallized inethanol-acetone mixture. The product was filtered off and dried in vacuoto give 0.15 g of ethyl(R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropionate. ¹ HNMR (CD₃ OD, 400 MHz): δ 1.11 (t,3H), 2.48 (s,3H), 2.52 (s,3H), 3.44(d,2H), 3.85 (d,2h) 4.24 (q,2H), 4.75 (t,1H), 7.76 (s,1H), 7.90 (s,1H),8.42 (d,1H).

Pharmaceutical Preparations

Pharmaceutical preparations containing a compound of the formula I aremade according to known methods. When the compounds are used asNMDA-antagonists a compound according to the invention is dissolved in aliquid diluent suitable for injection. It is especially preferred todissolve the compounds in isotonic sodium chloride solution. When thecompounds are used according to the invention it is also possible toadminister them in form of an oral or rectal preparation such astablets, capsules or suppositories. To produce pharmaceuticalpreparations containing a compound of the formula I in the form ofdosage units for oral administration the selected compound may be mixedwith a solid excipient, e.g. lactose or cellulose derivatives, a bindersuch as gelatine, and a lubricant such as magnesium stearate, and thencompressed into tablets. Dosage units for rectal application can besolutions or suspensions or can be prepared in the form ofsuppositories. Liquid preparations for oral application may be in theform of syrups or suspensions e.g. solutions containing from about 0.2%to about 20% by weight of the active substance herein described.Solutions for parenteral applications by injection can be prepared in anaqueous solution of a water-soluble pharmaceutically acceptable salt ofthe active substance. These solutions may optionally contain stabilizingagents and/or buffering agents and may conveniently be provided invarious dosage unit ampoules. Suitable unit dosages of the compounds ofthe invention in therapeutical treatment of human adults are from 10 to800 mg at peroral administration and 0.1 to 100 μg at intrathecaladministration.

Biological Evaluation

The compounds of the invention exhibit valuable pharmacologicalproperties, e.g. blocking the NMDA excitatory amino acid receptor inmammals. Thus, these novel compounds are useful in the treatment ofischemic conditions; stroke; brain or spinal cord injury;neurodegenerative disorders; Alzheimer, parkinsonian dementia orHuntington's disease; and convulsive disorders, such as epilepsy. Theyare also useful in the treatment of anxiety, schizofrenia, migraine,urinary incontinence, muscular spasms (spasticity); as analgesics and asanaesthetics; and for preventing withdrawal symptoms from drugs andalcohol. These effects are demonstrable in tests in vitro or in vivoe.g. in mice, rats, dogs or monkeys. Said compounds can be administeredto them orally or parenterally. The inhibitory effect on the NMDA-typeexcitatory amino acid receptors is determined in vitro by measuring theinhibition of the NMDA-evoked ³ H-acetylcholine release from corpusstriatum tissue of rat brain essentially as described by Lehmann andScatton, Brain Research, 252, 77 (1982). The inhibition of theNMDA-evoked ³ H-acetylcholine release from striatal tissue slices isexpressed as % of release of ³ H-acetylcholine in response tostimulation with 50 μM NMDA compared to control.

The inhibitory effect on the NMDA-type excitatory amino acid receptorsis determined also by an in vitro assay that measures the inhibition ofbinding of ³ H-CGS 19755 to brain tissue preparations essentiallyaccording to Lehmann et al., J. Pharmacol. Exptl. Therap., 246, 65(1988).

The anticonvulsive effect of the compounds of the invention isdetermined in vivo by inhibition of electroshock- or NMDA-inducedconvulsions in the mouse essentially as described in the last mentionedreference.

The analgetic effect of said compounds is determined in the rat and themouse by intrathecal injection essentially according to Cahusac et al.,Neuropharmacology, 23, 719 (1984).

I claim:
 1. A compound of formula (I) ##STR10## in which m is 0, 1 or2;n is 1, 2 or 3; R¹ and R² are, independently and being the same ordifferent, hydrogen, C₁ -C₇ alkyl, C₂ -C₇ alkenyl, C₄ -C₇ alkadienyl, C₆aryl, C₆ aryl-C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₁ -C₇ alkanoyl, C₁ -C₇alkanoyloxy, C₆ aroyl, C₆ aroyloxy, C₆ aryl-C₁ -C₇ alkanoyl, C₁ -C₇alkoxycarbonyl, C₆ aryl-C₁ -C₇ alkoxycarbonyl, C₁ -C₇ alkylthio,trifluoromethyl, trifluoromethoxy, C₁ -C₇ alkylsulfonylamino, C₁ -C₇alkylamino, C₁ -C₇ alkanoylamino, nitro, halogen, or R¹ and R² are,taken together, C₁ -C₇ alkylene, C₂ -C₇ alkenylene or C₄ -C₇alkadienylene, and pharmaceutically acceptable esters and salts,including hydrates, thereof.
 2. A compound according to claim 1, whereinsaid compound has the formula: ##STR11## and wherein R¹ and R² are asdefined in claim
 1. 3. A compound of formula (I) ##STR12## in which m is0, 1 or 2;n is 1, 2 or 3; R¹ and R² are, independently and being thesame or different, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₄ -C₆ alkadienyl,unsubstituted phenyl, phenyl substituted by one to three substituentsselected from the group consisting of: C₁ -C₇ alkyl, C₁ -C₇ alkoxy,trifluoromethyl and halogen, pyridyl, C₆ aryl-C₁ -C₄ -alkyl, C₁ -C₄alkoxy, C₂ -C₇ alkanoyl, C₂ -C₅ alkanoyloxy, benzoyl, benzoylsubstituted by one to three substituents selected from the groupconsisting of: C₁ -C₇ alkyl, C₁ -C₇ alkoxy, trifluoromethyl and halogen,pyridylcarbonyl, benzoyloxy, benzoyloxy substituted on the phenyl ringby C₁ -C₇ alkyl, halogen, C₁ -C₇ alkoxy, or nicotinoyloxy, fluorine,chlorine, trifluoromethyl, C₁ -C₄ alkanoylamino, C₁ -C₄ alkylamino, C₆aryl-C₁ -C₄ -alkanoyl, C₁ -C₄ alkoxylcarbonyl or C₆ aryl-C₁ -C₄alkoxylcarbonyl, or R¹ and R² are when taken together, C₂ -C₆ alkylene,C₂ -C₆ alkenylene, C₄ -C₆ alkadienylene.
 4. A compound according toclaim 1, wherein m is 1 and n is
 1. 5. A compound according to claim 1,wherein said compound is in the form of a substantially pure enantiomer.6. A compound according to claim 5, wherein said enantiomer is the(R)-isomer.
 7. A compound according to claim 1, wherein said compound isin the form of a salt of an alkali metal, alkaline earth metal or a saltof ammonia or an organic amine.
 8. A compound according to claim 1,wherein said compound is in the form of an ester selected from the groupconsisting of: C₁ -C₇ alkyl, C₆ aryl-C₁ -C₇ alkyl, C₁ -C₇alkanoyloxymethyl, C₁ -C₇ alkylamino-straight chain C₂ -C₄ alkyl.
 9. Acompound according to claim 8, wherein said ester is2-diethyl-aminoethyl.
 10. A compound according to claim 1, wherein saidcompound is selected from the group consistingof:α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acid;α-amino-2-(phosphonomethyl)-3-quinolinepropanoic acid;α-amino-6-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-7-ethoxy-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-7-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;α-amino-6,7-dimethoxy-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-7-methyl-3-(phosphonomethyl)-2-quinolinepropanoic acidhydrochloride;(R)-α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-5-chloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-6-fluoro-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-6,8-dichloro-3-(phosphonomethyl)-2-quinolinepropanoic acid;(R)-α-amino-7-chloro-6-methyl-3-(phosphonomethyl)-2-quinolinepropanoicacid;(R)-α-amino-6,7-diethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid;(S)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid;ethyl (R)-α-amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropionateacid.
 11. A compound according to claim 1, wherein said compoundis:(R)-α-Amino-6,7-dimethyl-3-(phosphonomethyl-2-quinolinepropanoicacid.
 12. A compound according to claim 1, wherein said compoundis:(R)-α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinolinepropanoicacid.
 13. A compound according to claim 1, wherein said compoundis:(R)-α-amino-6,7-diethyl-3-(phosphonomethyl)-2-quinolinepropanoicacid.
 14. A process for the preparation of a compound of formula (I),according to claim 1, comprising:a) reacting with a glycine anionequivalent in which amino and carboxylic acid moieties have protectinggroups that prevent their entering into reaction, a compound of formula(VI): ##STR13## in which R₃ is C₁ -C₇ alkyl, C₆ aryl or C₆ aryl C₁ -C₇alkyl; and b) removing said protecting groups from the product of stepa) to produce said compound of formula I.
 15. A process for thepreparation of a compound of formula (I), according to claim 1,comprising:a) reacting with a trialkyl phosphite, a compound of formula(VII): ##STR14## in which the amino and the carboxylic acid groups ofsaid compound of formula (VII) have protecting groups that prevent theirentering into reaction; and b) removing said protecting groups from theproduct of step a) to produce said compound of formula I.
 16. A processfor the preparation of a compound of formula (I), according to claim 1,comprising:a) reacting with a 2-amidoacrylate having protecting groupsto prevent reaction, a compound of formula (VIII): ##STR15## b)hydrogenating the compound formed in step a); and c) removing saidprotecting groups from the compound formed in step b).
 17. A process forthe preparation of a compound of formula (I), according to claim 1,comprising:a) reacting with a metallated β-iodoalanine having protectinggroups to prevent reaction, a compound of formula (VIII): b) removingsaid protecting groups.
 18. A pharmaceutical composition, comprising acompound of formula (I), according to claim 1, as an active ingredienttogether with a pharmaceutically acceptable carrier.
 19. Apharmaceutical composition according to claim 18, wherein said activeingredient is a salt of said compound.
 20. A pharmaceutical compositionaccording to claim 18, wherein said active ingredient is an ester ofsaid compound.
 21. A pharmaceutical composition according to claim 18,wherein said active ingredient is a hydrate of said compound.
 22. Apharmaceutical composition according to claim 18, wherein said activeingredient is an enantiomer of said compound.
 23. A pharmaceuticalcomposition according to claim 18, wherein said active ingredient is the(R)-enantiomer of said compound.
 24. A method for the treatment of asubject suffering from overstimulation of excitatory amino acidreceptors of the nervous system, comprising: administering an effectiveamount of a compound according to claim 1 to said subject.
 25. A methodfor the treatment of pain in a subject in need of such treatment,comprising:administering an effective amount of a compound according toclaim 1 to said subject.
 26. A method for the treatment of ischemicconditions in a subject in need of such treatment, comprising:administering an effective amount of a compound according to claim 1 tosaid subject.
 27. The method of claim 26, wherein said ischemiccondition is the result of a stroke.
 28. The method of claim 26, whereinsaid ischemic condition is the result of brain or spinal cord injury.29. A method for the treatment of neurodegenerative disorders in asubject in need of such treatment, comprising: administering aneffective amount of a compound according to claim 1 to said subject. 30.The method of claim 29, wherein said neurodegenerative disorder isAlzheimer's disease.
 31. The method of claim 29, wherein saidneurodegenerative disorder is Parkinsonian dementia.
 32. The method ofclaim 29, wherein said neurodegenerative disorder is Huntington'sdisease.
 33. A method for the treatment of convulsive disorders in asubject in need of such treatment, comprising: administering aneffective amount of a compound according to claim 1 to said subject. 34.The method of claim 33, wherein said convulsive disorder is epilepsy.35. A method for the treatment of anxiety in a subject in need of suchtreatment, comprising: administering an effective amount of a compoundaccording to claim 1 to said subject.
 36. A method for the treatment ofschizophrenia in a subject in need of such treatment, comprising:administering an effective amount of a compound according to claim 1 tosaid subject.
 37. A method for the treatment of migraine in a subject inneed of such treatment, comprising: administering an effective amount ofa compound according to claim 1 to said subject.
 38. A method for thetreatment of urinary incontinence in a subject in need of suchtreatment, comprising: administering an effective amount of a compoundaccording to claim 1 to said subject.
 39. A method for the treatment ofmuscular spasms in a subject in need of such treatment, comprising:administering an effective amount of a compound according to claim 1 tosaid subject.
 40. A method for the treatment of hearing loss in asubject in need of such treatment, comprising: administering aneffective amount of a compound according to claim 1 to said subject. 41.A method for the treatment of motor neuron diseases in a subject in needof such treatment, comprising: administering an effective amount of acompound according to claim 1 to said subject.
 42. A method for thetreatment of trauma from infections in a subject in need of suchtreatment, comprising: administering an effective amount of a compoundaccording to claim 1 to said subject.
 43. A method for preventingwithdrawal symptoms from drugs or alcohol in a subject in need of suchtreatment or prevention, comprising: administering an effective amountof a compound according to claim 1 to said subject.